A novel NF-L mutation Pro22Ser is associated with CMT2 in a large Slovenian family

Charcot-Marie-Tooth (CMT) disease is the most-common form of inherited motor and sensory neuropathy. The autosomal dominant axonal form of the disease (CMT2) is currently subdivided into seven types based on genetic localization. These are CMT2A (1p35-p36), CMT2B (3q13-q22), CMT2C (unknown), CMT2D (7p14), CMT2E (8p21), HMNSP (3q13.1), and CMT2F (7q11-q21). Two loci have thus far been identified for autosomal recessive CMT2; ARCMT2A (1q21.1-q21.3) and ARCMT2B (19q13.3). Mutations in four genes (connexin 32, myelin protein zero, neurofilament-light, and kinesin) have been associated with the CMT2 phenotype. We identified a novel neurofilament-light missense mutation (C64T) that causes the disease in a large Slovenian CMT2 family. This novel mutation shows complete co-segregation with the dominantly inherited CMT2 phenotype in our family. Electronic Publication     

Spinal neurofibromatosis in a family with classical neurofibromatosis type 1 and a novel NF1 gene mutation

Familial spinal neurofibromatosis (FSNF) is a rare form of neurofibromatosis type 1 (NF1) characterized by multiple, histologically proven neurofibromas of the spinal roots leaving no intact segments and associated neurofibromas of major peripheral nerves. It is sometimes associated with other NF1 stigmata. Most patients have NF1 gene mutations. We describe a patient who fulfilled the diagnostic criteria for spinal neurofibromatosis and belonged to a family in which other affected members exhibited classical NF1 stigmata. A novel missense (c.7109 T > A; p.Val2370Asp) mutation in exon 39 of the NF1 gene was present in the affected family members. The family displayed extreme phenotypic variability in the spectrum of NF1. To our knowledge, this is the first patient with spinal neurofibromatosis in the context of classical NF1 with an NF1 gene mutation. The term FSNF is inaccurate as this condition simply reflects the typical autosomal dominant pattern of NF1 inheritance with phenotypoc variability and does not encompass patients with sporadic disease or those in the context of a classical NF1 phenotype as reported in the present family. The term could be replaced by “spinal neurofibromatosis”.     

A novel mutation in sphingosine-1-phosphate lyase causing congenital brain malformation

Introduction

Recently recessive mutations in sphingosine-1-phosphate lyase (SGPL1) have been published as a cause of syndromic congenital nephrotic syndrome with adrenal insufficiency. We have identified a case with fetal hydrops and brain malformations due to a mutation in SGPL1.

Clinicopathologic and genetic analysis of siblings with NF1 and adult-onset gliomas

BACKGROUND: Neurofibromatosis Type 1 (NF1) is a common autosomal dominant neurogenetic disorder characterized by neoplasms involving the nervous system which typically present in children. The development of intracranial tumors in adults with NF1 is uncommon and to our knowledge, siblings with adult onset gliomas have not been previously reported. OBJECTIVE: To perform pathological, clinical and genetic analysis of an unusual family with NF1 and adult onset intracranial gliomas. RESULTS: A 39-year-old woman presented with seizures and aphasia and was diagnosed with an intracerebral tumor. Although there was no family history, she met the accepted clinical criteria for NF1. A biopsy was performed and pathological examination revealed an anaplastic pleomorphic xanthoastrocytoma (PXA). In spite of therapy, she died from complications of tumor recurrence. Her 32-year-old sister developed headaches and was diagnosed with a glioma. Although she did not meet the accepted clinical criteria for NF1, given that she has a sibling with NF1 and a malignancy observed in this disorder, we hypothesize that she also has NF1. Our genetic analysis indicated a shared haplotype in these siblings who developed brain tumors but not in an unaffected sister suggesting that both carry the NF1 disease-producing allele. This haplotype was inherited from their unaffected father indicating a paternal origin of the spontaneous putative mutation in the NF1 gene in this family. CONCLUSION: NF1 should be a diagnostic consideration when siblings develop intracranial brain tumors even when they develop in adults. Our study supports and extends other reports that broaden the clinical and pathological spectrum of manifestations that can occur in NF1 to include not only adult-onset gliomas but uncommon histological subtypes such as PXA.     

GNE myopathy in a Chinese male with a novel homozygous mutation

GNE myopathy is a rare autosomal recessive inheritance disease due to the mutation of GNE gene. To date, 107 mutations have been reported in different populations worldwide in GNE gene(HGMD Professional 2016.2). Here we report a patient of novel homozygous GNE gene mutation from China.     

中国人Ⅰ型神经纤维瘤病基因突变分析

目的对中国人Ⅰ型神经纤维瘤病（NF1）基因20、28、29、39号外显子进行基因突变分析及评价聚合酶链反应-单链构象多态／异源双链（PCR-SSCP／HA）技术在NFl基因诊断中的价值。方法应用PCR—SSCP／HA技术，结合DNA测序，筛查56例患者NF1基因20、28、29、39号外显子的突变或多态性。结果在20号外显子发现一个家系父子3人的SSCP／HA出现泳动异常，DNA测序证实为20号外显子上T—G的杂合突变即Leul 141Arg错义突变；发现1例患者28号外显子的SSCP／HA检测有泳动异常，测序证实为28号外显子5’端上游的第28位核苷酸G—T杂合；29、39号外显子未检测到泳动异常的条带。结论联合应用SSCP／HA的方法可提高基因突变检测敏感度及检出率，NF1基因20、28、29、39号外显子不是突变热点或突变率相对较高的区域。     

A novel CCM1 gene mutation causes cerebral cavernous malformation in a Chinese family

Familial cerebral cavernous malformations (CCMs) are characterized by an autosomal dominant transmission with incomplete penetrance. We have previously reported a 1292delAT mutation in the CCM1 gene in a Chinese family with CCM. Here we report a novel deletion of CCM1 that correlates strongly with CCM formation in another family. Ten affected family members were observed among the 25 participants, and multiple CCM lesions were detected in seven individuals. Nucleotide sequencing analysis in the index patient and other affected members showed a CAAA deletion in exon 12 at nucleotide (NT) 1197. We predict this deletion produces a premature stop code (TGA) at NT 1228, resulting in a truncated protein of 409 amino acids.     

A novel mutation of LRSAM1 in a Chinese family with Charcot‐Marie‐Tooth disease

Charcot‐Marie‐Tooth (CMT) disease is the most common inherited peripheral neuropathy characterized by progressive distal muscle weakness and atrophy with decreased or absent tendon reflexes. Mutations in LRSAM1 have been identified to cause CMT disease type 2P. We report a novel LRSAM1 mutation c.2021‐2024del (p.E674VfsX11) in a Chinese autosomal dominant CMT disease type 2 family. The phenotype was characterized by late onset and mild sensory impairment. Electrophysiological findings showed normal or mildly to moderately reduced motor and sensory nerve conduction velocities in lower and upper limb nerves.     

A novel de novo mutation of the mitochondrial tRNAlys gene mt.8340G>A associated with pure myopathy

Most patients with mutations in the tRNA^lys gene (MTTK) present with symptoms from the central nervous system (CNS). We describe a 41-year-old woman with pure myopathy associated with a novel de novo mtDNA mutation, mt.8340G>A, which was heteroplasmic in muscle (53%), blood, urine and mouth epithelial cells (<7%). No other family members, including her mother, carried the mutation. She presented with exercise intolerance from age 9, and since age 20 she experienced ptosis and reduced ocular motility. A muscle biopsy revealed ragged red fibres (10%), no COX negative fibres, and many fibres with central nuclei (30%), indicating ongoing damage and repair. The present case expands the mutational and phenotypic spectrum of diseases associated with mutations in MTTK.     

Exome capture sequencing identifies a novel CCM1 mutation in a Chinese family with multiple cerebral cavernous malformations

Purpose: Cerebral cavernous malformations (CCMs) are vascular anomalies predominantly in the central nervous system but may include lesions in other tissues, such as the retina, skin and liver. The main clinical manifestations include seizures, hemorrhage, recurrent headaches and focal neurological deficits. Previous studies of familial CCMs (FCCMs) have mainly reported in Hispanic and Caucasian cases. Here, we report on FCCMs in a Chinese family further characterized by a novel CCM1 gene mutation. Materials and methods: We investigated clinical and neuroradiological features of a Chinese family of 30 members. Furthermore, we used exome capture sequencing to identify the causing gene. The CCM1 mRNA expression level in three patients of the family and 10 wild-type healthy individuals were detected by real-time quantitative polymerase chain reaction (real-time RT-PCR). Results: Brain magnetic resonance imaging demonstrated multiple intracranial lesions in seven members. The clinical manifestation of CCM was found in five of these cases, including recurrent headaches, weakness, hemorrhage and seizures. Moreover, we identified a novel nonsense mutation c.1159G>T (p. E387*) in the CCM1 gene in the pedigree. Based on real-time RT-PCR results, we have found that the CCM1 mRNA expression level in three patients was reduced by 35% than that in wild-type healthy individuals. Conclusions: Our finding suggests that the novel nonsense mutation c.1159G>T in CCM1 gene is associated with FCCM, and that CCM1 haploinsufficiency may be the underlying mechanism of CCMs. Furthermore, it also demonstrates that exome capture sequencing is an efficient and direct diagnostic tool to identify causes of genetically heterogeneous diseases.     

A novel NF1 gene mutation in an Italian family with neurofibromatosis type 1

Purpose

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with an estimated incidence of one in 3,500 births. Clinically, NF1 is characterized by café-au-lait (CAL) spots, neurofibromas, freckling of the axillary or inguinal region, Lisch nodules, optic nerve glioma, and bone dysplasias. NF1 is caused by inactivating mutations of the 17q11.2-located NF1 gene. We present a clinical and molecular study of an Italian family with NF1.

Methods

The proband, a 10-year-old boy, showed large CAL spots and freckling on the axillary region and plexiform neurofibromas on the right side only. His father (47?years old) showed, in addition to the similar signs, numerous neurofibromas of various sizes on his thorax, abdomen, back, and shoulder. Two additional family members (a brother and a sister of the proband) presented only small CAL spots. The coding exons of NF1 gene were analyzed for mutations by denaturing high-performance liquid chromatography and sequencing in all family members.

Results

The mutational analysis of the NF1 gene revealed a novel frameshift insertion mutation in exon 4c (c.654 ins A) in all affected family members. This novel mutation creates a shift on the reading frame starting at codon 218 and leads to the introduction of a premature stop at codon 227.

Conclusions

The segregation of the mutation with the affected phenotype and its absence in the 200 normal chromosomes suggest that it is responsible for the NF1 phenotype.     

A novel deletion mutation in GJB1 causes X-linked Charcot-Marie-Tooth disease in a Han Chinese family

X-linked Charcot-Marie-Tooth disease CMT (CMTX) is predominantly caused by mutations in the GJB1 gene that encode connexin32. We describe the clinical findings and the identification of a novel mutation in GJB1 in a large Han Chinese family with CMTX. Linkage to GJB1 was determined by genotyping five polymorphic markers flanking GJB1. Sequence alterations were determined by directly sequencing the coding region of the GJB1 gene. The affected members have variable clinical manifestations. Linkage analysis confirmed the cosegregation of the disease with the GJB1 locus. Sequencing of the GJB1 gene revealed a 1-basepair deletion (c.110delT) in the coding region. The frameshift begins at amino acid 37 and generates a premature stop codon at position 83. The shortened peptide is unlikely to be functional, as it lacks most of the functional domains. The CMTX in this family is caused by a novel loss of function mutation.     

Cerebral vasculopathy in a Chinese family with neurofibromatosis type I mutation

Neurofibromatosis type I (NF1) is a hereditary, autosomal dominant, neurocutaneous syndrome that is attributed to NF1 gene mutation. NF1 has been associated with scoliosis, macrocephaly, pseudoarthrosis, short stature, mental retardation, and malignancies. NF1-associated vasculopathy is an uncommon and easily-overlooked presentation. Examination of a Chinese family affected by NF1 combined with cerebral vessel stenosis and/or abnormality suggested a possible relationship between NF1 and vessel stenosis. To determine which NF1 gene mutation is associated with vascular lesions, particularly cerebral vessel stenosis, we examined one rare family with combined cerebral vessel lesions or maldevelopment. Vascular lesions were detected using transcranial Doppler sonography and digital subtraction angiography in family members. Next, denaturing high-performance liquid chromatography and sequencing were used to screen for NF1 gene mutations. The results revealed a nonsense mutation, c.541C>T, in the NF1 gene. This mutation truncated the NF1 protein by 2659 aminoacid residues at the C-terminus and co-segregated with all of the patients, but was not present in unaffected individuals in the family. Exceptionally, three novel mutations were identified in unaffected family members, but these did not affect the product of the NF1 gene. Thus the nonsense mutation, c.541C>T, located in the NF1 gene could constitute one genetic factor for cerebral vessel lesions.     

Novel de novo splice-site mutation of SCN1A in a patient with partial epilepsy with febrile seizures plus

This report describes a 4-year-old male patient experienced prolonged febrile seizures after 1 year of age, multiple febrile seizures and complex partial seizures with secondary generalization. The gene encoding voltage-gated sodium channel alpha1-subunit: SCN1A analysis revealed a heterozygous de novo one-point mutation (IVS16+2 T>C) at a splice-acceptor site. This mutation was inferred to cause truncation of the alpha1-subunit molecule and, thereby, a loss of channel function. To date, truncation mutation has been found exclusively in patients with severe myoclonic epilepsy in infancy (SMEI), although only missense mutations have been found in generalized epilepsy with febrile seizures plus (GEFS+), partial epilepsy with FS+, FS+, and FS. The patient's phenotype is consistent with that of partial epilepsy with FS+, rather than SMEI, including borderline SMEI (SMEB). We present the first case report of partial epilepsy with FS+ associated with a truncation mutation of SCN1A. The possibility exists for concomitant involvement of multiple genes other than SCN1A for seizure phenotypes.     

A novel insertion mutation in spastin gene is the cause of spastic paraplegia in a Chinese family

A total of eight loci for autosomal dominant hereditary spastic paraplegia (ADHSP) has been mapped to chromosome 14q, 2p, 15q, 8q, 10q, 12q, 19q, 2q, respectively, among which the SPG4 gene on chromosome 2p21–22 encoding spastin, an ATPase of the AAA family, accounts for 40–50% of all ADHSP families and is expressed in both adult and fetal tissues. In this work, we reveal a novel insertion mutation in exon 11 of the SPG4 gene found in a big Chinese family composed of 47 members, including 20 affected ones, using linkage analysis. The mutation was well demonstrated to be the cause of loss of production of the functional protein by pre-termination of translation in AAA cassette region. To our knowledge, this is the first report of spastin mutation in China.     

Mucolipidosis type IV in a Turkish boy associated with a novel MCOLN1 mutation

Mucolipidosis type IV is a rare neurodegenerative lysosomal storage disorder that usually presents during the first year of life with severe mental retardation, delayed motor milestones and corneal opacities. Mucolipidosis IV is caused by mutations in MCOLN1, a gene encoding mucolipin-1 which is responsible for maintaining lysosomal function. The majority of known patients with this disorders are Ashkenazi Jews, and most have a splice IVS3-2 A>G, or a 6.4 kb deletion mutation in MCOLN1. Here, we present a Turkish patient who, in addition to the typical neurological and visceral characteristics of mucolipidosis type IV, also demonstrates defects in the posterior limb of internal capsule by MRI, micrognathia and clinodactyly of the fifth fingers. Direct sequencing of his DNA revealed a homozygous c.1364C>T (S456L) mutation in MCOLN1, which was heterozygous in both consanguineous parents. This mutation, like several previously described, changes the protein sequence in the channel pore domain of the protein. Serine 456 is conserved in mucolipin proteins throughout evolution, therefore the mutation is considered as causative for the severe phenotype of this patient.     

Prenatal diagnosis of citrullinemia type 1: A Chinese family with a novel mutation of the ASS1 gene

Background

Argininosuccinate synthetase deficiency (citrullinemia type 1) is a rare autosomal recessive disorder of the urea cycle characterized by elevated concentrations of citrulline, ammonia, and orotic acid, manifesting with acute hyperammonemic crises, usually early in life, with concurrent neurologic deterioration. Only a few cases of citrullinemia type 1 have been documented from mainland China. Prenatal diagnosis has not been performed.

Methods

A Chinese family affected by citrullinemia type 1 was studied. The proband, a girl, was the second child born to a non-consanguineous couple. Her elder brother died at 19 months due to coma and liver dysfunction of unknown cause. The proband was admitted because of severe mental retardation and lethargy at the age of 15 months. Initial laboratory results revealed hyperammonaemia, hypercitrullinemia (928.771 μmol/L, normal 5.0–25.0 μmol/L) and orotic aciduria, supporting the diagnosis of citrullinemia type 1. Subsequently, the mother presented at 15 weeks of pregnancy seeking for genetic counseling and prenatal diagnosis. ASS1 gene in the blood leukocytes of the family members and amniocytes was performed by direct sequencing.

Results

On the ASS1 gene of the proband, a novel mutation, T1009C (C337R), and a previously reported mutation G847A (E283K) were identified. Each parent carries one of two mutations. G847A and T1009C mutations were detected in amniocytes, as same as the proband of the family. The result revealed that the fetus was affected by argininosuccinate synthetase deficiency. The parents chose to have a termination of the pregnancy.

Conclusions

Prenatal diagnosis for citrullinemia type 1 was performed in a Chinese family using gene analysis. T1009C (C337R), a novel mutation of ASS1, was identified.     

Progressive ataxia associated with ocular apraxia type 1 (AOA1) with a presence of a novel mutation on the aprataxin gene

Ataxia, although rare, can be a symptom of many debilitating movement disorders. Hereditary ataxias are one subset of this condition and manifest when there is a genetic abnormality involved. Ataxia oculomotor apraxia type 1 (AOA1), an autosomal recessive ataxia, results from a mutation on the aprataxin gene (APTX). We characterized a novel homozygous deletion mutation (IVS4-12delT) on the APTX gene in a 14-year-old male born to consanguineous parents. This case report emphasizes the importance of investigating and increasing awareness of novel genetic mutations in order to help diagnose and further classify hereditary ataxias.     

Aceruloplasminemia: A novel mutation in a family with marked phenotypic variability

Hereditary aceruloplasminemia (HA) is a rare inherited disease characterized by anemia, iron overload, diabetes, and neurodegeneration. HA is caused by the homozygous mutation of the ceruloplasmin (CP) gene. We report two siblings with markedly different phenotypes carrying a novel mutation: a homozygous deletion of two nucleotides (1257–1258 TT del) causing the premature stop of the Cp protein translation (Y401X). An early diagnosis of iron overload was made in the female sibling who was subsequently treated with deferoxamine. At the age of 54, her neurologic symptoms were limited to mild akinetic signs and a history of seizures; moreover, her fasting blood glucose level never exceeded 120 mg/dL. The male sibling, who had not received any specific treatment for HA, developed severe diabetes at the age of 32 and at 48 manifested a progressively disabling neurologic disease. Possible physiopathological bases of these intrafamilial phenotypic variations are discussed. © 2008 Movement Disorder Society